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Administrative data

Workers - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
8.01 mg/m³
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
Oral
DNEL related information
DNEL derivation method:
other: substance specific, see discussion
Overall assessment factor (AF):
33
Dose descriptor starting point:
NOAEL
Value:
150 mg/kg bw/day
Modified dose descriptor starting point:
NOAEC
Value:
264.5 mg/m³
Explanation for the modification of the dose descriptor starting point:

The calculation of the DNEL is based on an oral NOAEL observed in a combined repeated dose oral toxicity study with the reproduction/developmental toxicity screening test (OECD 422; METI 2012).

To correct the interspecies difference between rat and human the no observed effect level has to be corrected as follows:

Corrected starting point for the inhalative route for workers:

= NOAEL(oral) * (1/0.38 m³/kg bw/day) * (ABSoral-rat/ABSinh-human) * 6.7 m³ (8h) /10 m³ (8h)

= 150 mg/kg bw/day * (1/0.38 m³/kg bw/day) * (1/1) * 0.67 m³ = 264.5 mg/m³

In contrast to the recommendations of the ECHA Guidance, a factor of 1 (equal absorption of 100% assumed for the oral and the inhalative route for animals and humans) was included for the extrapolation from oral to inhalation absorption, as there is no valid data suggesting that inhalation leads to higher absorption than oral ingestion (recommendation of the VCI Working group "Toxicology", 2008). Molecules with a molecular weight <500 and a log Kow between 0 and 4 can be assumed to be well absorbed equivalently by the oral and inhalation route. Oral absorption may be reduced for acids and bases depending on their pKa value and their electric charge in the GI tract. More lipophilic substances may be better absorbed in the GI tract due to solubilisation with bile acids, and thus oral absorption may be higher than inhalation absorption (VCI Working group "Toxicology", 2008). Unless valid data suggest that inhalation leads to higher absorption than oral ingestion, equal absorption will be assumed when extrapolating from oral to inhalation route.

(ABSoral-rat = oral absorption in rats, ABSinh-human = inhalation absorption rate in humans)

Thus, the corrected starting point for workers was 264.5 mg/m³ for inhalation.

AF for dose response relationship:
1
Justification:
The dose descriptor starting point is based on a NOAEL.
AF for differences in duration of exposure:
6
Justification:
based on a subacute study
AF for interspecies differences (allometric scaling):
1
Justification:
AF is not used for inhalation route.
AF for other interspecies differences:
2.5
Justification:
default
AF for intraspecies differences:
2.2
Justification:
substance specific, see discussion
AF for the quality of the whole database:
1
Justification:
The DNEL is based on a high-quality study.
AF for remaining uncertainties:
1
Justification:
No remaining uncertainties.
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
Most sensitive endpoint:
acute toxicity
Route of original study:
By inhalation
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
no hazard identified
Most sensitive endpoint:
skin irritation/corrosion
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

Workers - Hazard via dermal route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
4.55 mg/kg bw/day
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
Oral
DNEL related information
DNEL derivation method:
other: substance specific, see discussion
Overall assessment factor (AF):
33
Dose descriptor starting point:
NOAEL
Value:
150 mg/kg bw/day
Modified dose descriptor starting point:
NOAEL
Value:
150 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:

No data are available for the dermal route. However, reliable data are available for the oral route (OECD 422, METI 2012).

Dermal NOAEL = oral NOAEL*ABS(oral)/ABS(dermal) = 150 mg/kg bw/day *(1/1) = 150 mg/kg bw/day. It is assumed that oral and dermal absorption rates are equal.

AF for dose response relationship:
1
Justification:
The dose descriptor starting point is based on a NOAEL.
AF for differences in duration of exposure:
6
Justification:
based on a subacute study
AF for interspecies differences (allometric scaling):
1
Justification:
substance specific, see discussion
AF for other interspecies differences:
2.5
Justification:
default
AF for intraspecies differences:
2.2
Justification:
substance specific, see discussion
AF for the quality of the whole database:
1
Justification:
The DNEL is based on a high-quality study.
AF for remaining uncertainties:
1
Justification:
No remaining uncertainties.
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
no hazard identified
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified

Workers - Hazard for the eyes

Local effects

Hazard assessment conclusion:
no hazard identified

Additional information - workers

Short-term high exposures are considered unlikely given the high levels of control in place at sites producing and using the substance. DNELs for long-term exposure are therefore adequate to protect against short-term exposures and no separate short-term DNELs are calculated for workers. No oral exposure will occur during occupational handling and use therefore DNELs via the oral route are not calculated for workers.

DNELs for long-term exposure are protective against short-term exposures and no separate short-term DNELs are calculated for the general population.

Dermal and inhalation DNELs are calculated for both workers and general population.

A DNEL for the oral route is calculated for the general population, for the assessment of exposure via the environment.

No DNELs for local effects after short-term and long-term exposure were calculated, as no relevant effects were identified.

Correction of dose descriptors for each relevant endpoint is described below

Workers

Repeated dose toxicity – systemic effects – dermal route – worker:

The long-term DNEL for systemic effects via the dermal route is determined on the basis of route-to-route extrapolation from the NOAEL (150 mg/kg bw/day) from a OECD 422 study by oral route in rats. The following corrections were made:

Correction for route to route extrapolation (relative absorption oral vs. dermal): 1

The corrected NOAEL (dermal) is therefore:

150 mg/kg bw/day × 1 = 150 mg/kg bw/day

 

The following assessment factors were applied to the corrected NOAEL:

Exposure duration (sub-acute to chronic): 6 (default)

Interspecies differences (remaining differences): 2.5 (default)

Interspecies differences (toxicokinetics, rat/human): 1 (substance-specific, see below)

Intraspecies differences (worker): 2.2 (substance-specific, see below)

Total AF: 6×2.5×1×2.2=33

Allometric scaling factor (Toxicokinetics)

The allometric scaling factor accounts for metabolic differences between the test species and humans. This factor is not considered to be relevant for triethoxy(methyl)silane on the following grounds:

1.       The silanol hydrolysis product of the substance (and many other related substances) shows no biodegradation in a ready biodegradation test other than can be accounted for by degradation of non-silanol hydrolysis products; this suggests that the substance and its silanol hydrolysis product are not recognised by biological systems containing all the mammalian enzymes and metabolic systems (see section 4.1.2).

2.       Toxicokinetic arguments show that the silanol hydrolysis product has low log Kow and hence low uptake, rapid excretion via urine, which would be true in all mammals, with minimal interspecies differences.

3.       Higher enzyme expression levels, stronger inducibility, higher substrate affinities and co-factor levels are factors that are potentially in favour of a more rapid xenobiotic metabolism, including elimination, by rodents compared to humans. Enzymes are not involved in the abiotic hydrolysis of the alkoxysilanes, and the silanols are rapidly excreted as such without prior enzymatic conjugation. This knowledge eliminates a great deal of the uncertainty on toxicokinetic interspecies differences.Since the metabolism of triethoxy(methyl)silane by humans and rats does not involve enzymes, the toxicokinetic differences (both inter- and intraspecies) are reduced from 4.0 to 1.0. Only the toxicodynamic differences remain to be considered.

 

Intraspecies differences

The intraspecies assessment factor takes account for the variability in sensitivity between individuals. The human population is far more diverse than experimental animals that are bred to be as similar as possible, and unhealthy animals are not allowed to start the study. This AF also covers differences between ethnic groups and age groups. The default intraspecies factors are typically broken down into equal factors accounting for toxicodynamic and toxicokinetic differences, respectively. Accordingly, an interspecies factor of 10 is composed of two identical factors of √10 = 3.2.

Likewise, the default for workers (AF = 5) can be split into AFs of √5 = 2.2. As discussed above, the conversion of siloxanes to silanols and their excretion proceeds without enzymatic involvement. Individual genetic dispositions and other are therefore without effect on these processes. As a result, the toxicokinetic components (3.2 and 2.2 for general population and workers, respectively) can be eliminated from the intraspecies AF for substances that hydrolyse fast into the ultimate excretion product.

 

The overall DNEL (repeated-dose – systemic – dermal - worker) is therefore:

150 mg/kg bw/day / 33 = 4.55 mg/kg bw/day.

Repeated dose toxicity – systemic effects – inhalation route – worker:

The long-term DNEL for systemic effects via the inhalation route is determined on the basis of route-to-route extrapolation from the NOAEL (150 mg/kg bw/day) from a OECD 422 study by oral route in rats. The following corrections were made:

standard respiratory volume in rats for 8 hour exposure: 0.38 m³/kg bw

Correction for respiratory volume (worker, light physical activity): 6.7 m³/10 m³

Correction for route to route extrapolation (relative absorption oral vs. inhalation): 1/1

In contrast to the recommendations of the ECHA Guidance, a factor of 1 (equal absorption of 100% assumed for the oral and the inhalative route for animals and humans) was included for the extrapolation from oral to inhalation absorption, as there is no valid data suggesting that inhalation leads to higher absorption than oral ingestion (recommendation of the VCI Working group "Toxicology", 2008). Molecules with a molecular weight <500 and a log Kow between 0 and 4 can be assumed to be well absorbed equivalently by the oral and inhalation route. Oral absorption may be reduced for acids and bases depending on their pKa value and their electric charge in the GI tract. More lipophilic substances may be better absorbed in the GI tract due to solubilisation with bile acids, and thus oral absorption may be higher than inhalation absorption (VCI Working group "Toxicology", 2008). Unless valid data suggest that inhalation leads to higher absorption than oral ingestion, equal absorption will be assumed when extrapolating from oral to inhalation route.

Therefore the corrected NOAEC for long-term systemic effects via the inhalation route is:

150 mg/kg bw/day × (1/0.38 m³/kg/day×(1/1)×(6.7/10) = 264.5 mg/m³

The following assessment factors were applied to the corrected NOAEC:

Exposure duration (sub-acute to chronic): 6

Interspecies differences (remaining differences): 2.5

Interspecies differences (toxicokinetics, rat/human): 1 (substance-specific, see above)

Intraspecies differences (worker): 2.2 (substance-specific, see above)

Total AF: 6×2.5×1×2.2=33

 

The overall DNEL (repeated-dose – systemic – inhalation - worker) is therefore:

132.2 mg/m³ / 33 = 8.01 mg/m³.

 

General Population - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
2.72 mg/m³
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
Oral
DNEL related information
DNEL derivation method:
other: substance specific, see discussion
Overall assessment factor (AF):
48
Dose descriptor starting point:
NOAEL
Value:
150 mg/kg bw/day
Modified dose descriptor starting point:
NOAEC
Value:
130.4 mg/m³
Explanation for the modification of the dose descriptor starting point:

The calculation of the DNEL is based on an oral NOAEL observed from a combined repeated dose oral study with the reproduction/developmental toxicity screening test (OECD 422) in rats.

To correct the interspecies difference between rat and human the no observed effect level has to be corrected as follows:

Corrected starting point for the inhalative route for general population:

= NOAELoral * (1/1.15 m³/kg bw/day (24h)) * (ABSoral-rat / ABSinh-human)

= 150 mg/kg bw/day * (1/1.15 m³/kg bw/day) * (1/1) = 130.4 mg/m³

In contrast to the recommendations of the ECHA Guidance, a factor of 1 (equal absorption of 100% assumed for the oral and the inhalative route for animals and humans) was included for the extrapolation from oral to inhalation absorption, as there is no valid data suggesting that inhalation leads to higher absorption than oral ingestion (recommendation of the VCI Working group "Toxicology", 2008). Molecules with a molecular weight <500 and a log Kow between 0 and 4 can be assumed to be well absorbed equivalently by the oral and inhalation route. Oral absorption may be reduced for acids and bases depending on their pKa value and their electric charge in the GI tract. More lipophilic substances may be better absorbed in the GI tract due to solubilisation with bile acids, and thus oral absorption may be higher than inhalation absorption (VCI Working group "Toxicology", 2008). Unless valid data suggest that inhalation leads to higher absorption than oral ingestion, equal absorption will be assumed when extrapolating from oral to inhalation route.

(ABSoral-rat = oral absorption in rats, ABSinh-human = inhalation absorption rate in humans)

Thus, the corrected starting point for general population was 130.4 mg/m³ for inhalation.

AF for dose response relationship:
1
Justification:
The dose descriptor starting point is based on a NOAEL.
AF for differences in duration of exposure:
6
Justification:
based on a subacute study
AF for interspecies differences (allometric scaling):
1
Justification:
AF not used for inhalation route.
AF for other interspecies differences:
2.5
Justification:
default
AF for intraspecies differences:
3.2
Justification:
substance specific, see discussion
AF for the quality of the whole database:
1
Justification:
The DNEL is based on a high-quality study.
AF for remaining uncertainties:
1
Justification:
No remaining uncertainties.
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
no hazard identified
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

General Population - Hazard via dermal route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
3.13 mg/kg bw/day
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
Oral
DNEL related information
DNEL derivation method:
other: substance specific, see discussion
Overall assessment factor (AF):
48
Dose descriptor starting point:
NOAEL
Value:
150 mg/kg bw/day
Modified dose descriptor starting point:
NOAEL
Value:
150 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:

No data are available for the dermal route. However, reliable data are available for the oral route (OECD 422, METI 2012).

Dermal NOAEL = oral NOAEL*ABS(oral)/ABS(dermal) = 150 mg/kg bw/day *(1/1) = 150 mg/kg bw/day. Itis assumed that oral and dermal absorption rates are equal.

AF for dose response relationship:
1
Justification:
The dose descriptor starting point is based on a NOAEL.
AF for differences in duration of exposure:
6
Justification:
based on a subacute study
AF for interspecies differences (allometric scaling):
1
Justification:
substance specific, see discussion
AF for other interspecies differences:
2.5
Justification:
default
AF for intraspecies differences:
3.2
Justification:
substance specific, see discussion
AF for the quality of the whole database:
1
Justification:
The DNEL is based on a high-quality study.
AF for remaining uncertainties:
1
Justification:
No remaining uncertainties.
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
no hazard identified
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified

General Population - Hazard via oral route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
3.13 mg/kg bw/day
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
Oral
DNEL related information
DNEL derivation method:
other: substance specific, see discussion
Overall assessment factor (AF):
48
Dose descriptor starting point:
NOAEL
Value:
150 mg/kg bw/day
AF for dose response relationship:
1
Justification:
The dose descriptor starting point is based on a NOAEL.
AF for differences in duration of exposure:
6
Justification:
based on a subacute study
AF for interspecies differences (allometric scaling):
1
Justification:
substance specific, see discussion
AF for other interspecies differences:
2.5
Justification:
default
AF for intraspecies differences:
3.2
Justification:
substance specific, see discussion
AF for the quality of the whole database:
1
Justification:
The DNEL is based on a high-quality study.
AF for remaining uncertainties:
1
Justification:
No remaining uncertainties.
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

General Population - Hazard for the eyes

Local effects

Hazard assessment conclusion:
no hazard identified

Additional information - General Population

There is one oral repeated dose toxicity study availabe for triethoxy(methyl)silane (CAS 2031 -67 -6).

In the absence of any significant findings relating to reproductive or developmental endpoints in appropriate screening tests, the critical health effect is considered to be repeated-dose toxicity.

General population

Repeated dose toxicity – systemic effects – dermal route – general population:

The long-term DNEL for systemic effects via the dermal route is determined on the basis of route-to-route extrapolation from the NOAEL (150 mg/kg bw/day) from an OECD 422 study by oral route in rats (METI, 2012).

The following corrections were made:

Correction for route to route extrapolation (relative absorption oral vs. dermal): 1

The corrected NOAEL (dermal) is therefore: 150 mg/kg bw/day × 1 = 150 mg/kg bw/day.

 

The following assessment factors were applied to the corrected NOAEL:

Extrapolation of exposure duration (sub-acute to chronic): 6 (default)

Interspecies differences (toxicodynamics): 2.5 (default)

Interspecies differences (toxicokinetics, rat/human): 1 (substance-specific, see below)

Intraspecies differences (general population): 3.2 (substance-specific, see below)

Total AF: 6 × 2.5 × 1 × 3.2 = 48

 

 Allometric scaling factor (Toxicokinetics)

The allometric scaling factor accounts for metabolic differences between the test species and humans. This factor is not considered to be relevant for triethoxy(methyl)silane on the following grounds:

1.       The silanol hydrolysis product of the substance (and many other related substances) shows no biodegradation in a ready biodegradation test other than can be accounted for by degradation of non-silanol hydrolysis products; this suggests that the substance and its silanol hydrolysis product are not recognised by biological systems containing all the mammalian enzymes and metabolic systems.

2.       Toxicokinetic arguments show that the silanol hydrolysis product has low log Kow and hence low uptake, rapid excretion via urine, which would be true in all mammals, with minimal interspecies differences.

3.       Higher enzyme expression levels, stronger inducibility, higher substrate affinities and co-factor levels are factors that are potentially in favour of a more rapid xenobiotic metabolism, including elimination, by rodents compared to humans. Enzymes are not involved in the abiotic hydrolysis of the alkoxysilanes, and the silanols are rapidly excreted as such without prior enzymatic conjugation. This knowledge eliminates a great deal of the uncertainty on toxicokinetic interspecies differences. Since the metabolism of triethoxy(methyl)silane by humans and rats does not involve enzymes, the toxicokinetic differences (both inter- and intraspecies) are reduced from 4.0 to 1.0. Only the toxicodynamic differences remain to be considered.

 

Intraspecies differences

The intraspecies assessment factor takes account for the variability in sensitivity between individuals. The human population is far more diverse than experimental animals that are bred to be as similar as possible, and unhealthy animals are not allowed to start the study. This AF also covers differences between ethnic groups and age groups. The default intraspecies factors are typically broken down into equal factors accounting for toxicodynamic and toxicokinetic differences, respectively. Accordingly, an interspecies factor of 10 is composed of two identical factors of √10 = 3.2.

Likewise, the default for workers (AF = 5) can be split into AFs of √5 = 2.2. As discussed above, the conversion of siloxanes to silanols and their excretion proceeds without enzymatic involvement. Individual genetic dispositions and other are therefore without effect on these processes. As a result, the toxicokinetic components (3.2 and 2.2 for general population and workers, respectively) can be eliminated from the intraspecies AF for substances that hydrolyse fast into the ultimate excretion product.

 

The overall DNEL (long-term – systemic – dermal – general population) is therefore:

150 mg/kg bw/day / 48 = 3.13 mg/kg bw/day.

 

Repeated-dose toxicity - systemic effects - inhalation route - general population:

 

The long-term DNEL for systemic effects via the inhalation route is determined on the basis of the OECD 422 NOAEL (150 mg/kg bw/day, oral in rats). The following corrections were made:

standard respiratory volume in rats for 24 hours exposure: 1.15 m³/kg bw

Correction for route to route extrapolation (relative absorption oral vs. inhalation): 1/1

In contrast to the recommendations of the ECHA Guidance, a factor of 1 (equal absorption of 100% assumed for the oral and the inhalative route for animals and humans) was included for the extrapolation from oral to inhalation absorption, as there is no valid data suggesting that inhalation leads to higher absorption than oral ingestion (recommendation of the VCI Working group "Toxicology", 2008). Molecules with a molecular weight <500 and a log Kow between 0 and 4 can be assumed to be well absorbed equivalently by the oral and inhalation route. Oral absorption may be reduced for acids and bases depending on their pKa value and their electric charge in the GI tract. More lipophilic substances may be better absorbed in the GI tract due to solubilisation with bile acids, and thus oral absorption may be higher than inhalation absorption (VCI Working group "Toxicology", 2008). Unless valid data suggest that inhalation leads to higher absorption than oral ingestion, equal absorption will be assumed when extrapolating from oral to inhalation route.

Therefore the corrected NOAEC for long-term systemic effects via the inhalation route is:

150 mg/m³ × (1/1.15) × 1 = 130.4 mg/m³

The following assessment factors were applied to the corrected NOAEC:

Exposure duration (sub-acute to chronic): 6 (default)

Interspecies differences (remaining differences): 2.5 (default)

Interspecies differences (toxicokinetics, rat/human): 1 (substance-specific, see above)

Intraspecies differences (general population): 3.2 (substance-specific, see above)

Total AF: 6 × 2.5 × 1 × 3.2 = 48

 

The overall DNEL (long-term – systemic – inhalation – general population) is therefore:

130.4 mg/m³ / 48 = 2.72 mg/m³.

Repeated dose toxicity – systemic effects – oral route – general population:

The long-term DNEL for systemic effects via the oral route is determined on the basis of the 28-day oral NOAEL for the test substance (150 mg/kg bw/day).

The following assessment factors were applied to the corrected NOAEL:

Exposure duration (subacute to chronic): 6 (default)

Interspecies differences (toxicodynamics): 2.5 (default)

Interspecies differences (toxicokinetics, rat/human): 1 (substance-specific, see above)

Intraspecies differences (general population): 3.2 (substance-specific, see above)

Total AF: 6 × 2.5 × 1 × 3.2 = 48

 

The overall DNEL (long-term – systemic – oral – general population) is therefore:

150 mg/kg bw/day / 48 = 3.13 mg/kg bw/day.